ABSTRACT Short stature is a hallmark of several human Mendelian disorders caused by mutations in extracellular matrix (ECM) proteins. These include acromelic dysplasias, a group of rare disorders featuring short stature, short digits (brachydactyly), stiff joints, and a ?pseudomuscular? build. Acromelic dysplasias are caused by dominant mutations in specific exons of fibrillin-1 (FBN1) or by recessive mutations in select ADAMTS and ADAMTSL proteins. Relevant to this proposal, the identical clinical manifestations of ADAMTSL2 and FBN1 mutations in one such disorder, geleophysic dysplasia, suggests that their gene products cooperate in a shared ECM pathway regulating postnatal limb growth. Previous work showed that ADAMTSL2 is a secreted glycoprotein that bound both fibrillin isoforms, FBN1 and FBN2, and was implicated in the regulation of TGF? signaling. FBN2 microfibrils were increased in the ECM of a mouse model for geleophysic dysplasia, suggesting a role for ADAMTSL2 in switching from prenatal FBN2 microfibrils to postnatal FBN1 microfibrils. My preliminary data show that the limb-specific deletion of ADAMTSL2 in mice impairs skeletal growth similar to human acromelic dysplasias, with exacerbated distal limb shortening and reduced Achilles tendon length. ADAMTSL2 is not expressed in growth plate chondrocytes or bone cells, but has its strongest expression in tendon. This led to the hypothesis that non-autonomous postnatal growth impairment in a mouse model for geleophysic dysplasia is caused by the disruption of fibrillin microfibril function in tendon ECM due to impairment of the ADAMTSL2-mediated fibrillin isoform switch. Despite the rarity of geleophysic dysplasia, the non- autonomous regulation of skeletal growth governed by mechanical or regulatory properties of tendon ECM would constitute a novel mechanism determining final bone length. In aim 1, I will test the hypothesis by analysing postnatal limb growth and ECM alterations in the microfibril system after Adamtsl2 deletion in tenocytes (tendon) using Scx-Cre and in an Achilles tendon transection model. In aim 2, I will investigate how ADAMTSL2 interacts with FBN1 and FBN2 and how ADAMTSL2 executes its role in the isoform switch from FBN2 to FBN1. I will analyze the genetic interaction of Adamtsl2 with Fbn1 and Fbn2 in mice and I will use protein-protein interaction studies and cell culture systems to gain mechanistic insights in the function of ADAMTSL2 in regulating the fibrillin isoform switch. The anticipated results will provide novel insights into the pathophysiology of geleophysic dysplasia and are relevant to the pathophysiology of acromelic dysplasias and other human genetic disorders involving fibrillin microfibrils (fibrillinopathies). An important and related one among these is the Marfan syndrome, which affects 1-2 in 5000 individuals and shows long bone overgrowth. These insights could be translated in novel therapeutic strategies targeting the ECM during postnatal growth. In addition, this proposal addresses fundamental questions of how tissue-specific ECM is formed and how functional properties of soft tissues determined by ECM might regulate postnatal limb growth.